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Lack of beta-arrestin signaling in the absence of active G proteins

Author

Listed:
  • Manuel Grundmann

    (Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn)

  • Nicole Merten

    (Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn)

  • Davide Malfacini

    (Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn)

  • Asuka Inoue

    (Tohoku University
    PRESTO, Japan Science and Technology Agency (JST))

  • Philip Preis

    (Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn)

  • Katharina Simon

    (Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn)

  • Nelly Rüttiger

    (University Hospital Jena)

  • Nicole Ziegler

    (University of Wuerzburg)

  • Tobias Benkel

    (Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn)

  • Nina Katharina Schmitt

    (Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn)

  • Satoru Ishida

    (Tohoku University)

  • Ines Müller

    (Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn)

  • Raphael Reher

    (University of Bonn)

  • Kouki Kawakami

    (Tohoku University)

  • Ayumi Inoue

    (Tohoku University)

  • Ulrike Rick

    (Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn)

  • Toni Kühl

    (University of Bonn)

  • Diana Imhof

    (University of Bonn)

  • Junken Aoki

    (Tohoku University
    Japan Agency for Medical Research and Development)

  • Gabriele M. König

    (University of Bonn)

  • Carsten Hoffmann

    (University Hospital Jena)

  • Jesus Gomeza

    (Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn)

  • Jürgen Wess

    (Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK))

  • Evi Kostenis

    (Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn)

Abstract

G protein-independent, arrestin-dependent signaling is a paradigm that broadens the signaling scope of G protein-coupled receptors (GPCRs) beyond G proteins for numerous biological processes. However, arrestin signaling in the collective absence of functional G proteins has never been demonstrated. Here we achieve a state of “zero functional G” at the cellular level using HEK293 cells depleted by CRISPR/Cas9 technology of the Gs/q/12 families of Gα proteins, along with pertussis toxin-mediated inactivation of Gi/o. Together with HEK293 cells lacking β-arrestins (“zero arrestin”), we systematically dissect G protein- from arrestin-driven signaling outcomes for a broad set of GPCRs. We use biochemical, biophysical, label-free whole-cell biosensing and ERK phosphorylation to identify four salient features for all receptors at “zero functional G”: arrestin recruitment and internalization, but—unexpectedly—complete failure to activate ERK and whole-cell responses. These findings change our understanding of how GPCRs function and in particular of how they activate ERK1/2.

Suggested Citation

  • Manuel Grundmann & Nicole Merten & Davide Malfacini & Asuka Inoue & Philip Preis & Katharina Simon & Nelly Rüttiger & Nicole Ziegler & Tobias Benkel & Nina Katharina Schmitt & Satoru Ishida & Ines Mül, 2018. "Lack of beta-arrestin signaling in the absence of active G proteins," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02661-3
    DOI: 10.1038/s41467-017-02661-3
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    Cited by:

    1. Yulong Gong & Bingyuan Yang & Dingdong Zhang & Yue Zhang & Zihan Tang & Liu Yang & Katie C. Coate & Linlin Yin & Brittney A. Covington & Ravi S. Patel & Walter A. Siv & Katelyn Sellick & Matthew Shou , 2023. "Hyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Julian Brands & Sergi Bravo & Lars Jürgenliemke & Lukas Grätz & Hannes Schihada & Fabian Frechen & Judith Alenfelder & Cy Pfeil & Paul Georg Ohse & Suzune Hiratsuka & Kouki Kawakami & Luna C. Schmacke, 2024. "A molecular mechanism to diversify Ca2+ signaling downstream of Gs protein-coupled receptors," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    3. Evi Kostenis & Jesus Gomeza & Elke Miess-Tanneberg & Nina Kathleen Blum & Tobias Benkel & Andy Chevigné & Carsten Hoffmann & Peter Kolb & Viacheslav Nikolaev & Maria Waldhoer & Martyna Szpakowska & As, 2023. "Reply to: How carvedilol does not activate β2-adrenoceptors," Nature Communications, Nature, vol. 14(1), pages 1-3, December.
    4. Junke Liu & Hengmin Tang & Chanjuan Xu & Shengnan Zhou & Xunying Zhu & Yuanyuan Li & Laurent Prézeau & Tao Xu & Jean-Philippe Pin & Philippe Rondard & Wei Ji & Jianfeng Liu, 2022. "Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Dylan Scott Eiger & Noelia Boldizsar & Christopher Cole Honeycutt & Julia Gardner & Stephen Kirchner & Chloe Hicks & Issac Choi & Uyen Pham & Kevin Zheng & Anmol Warman & Jeffrey S. Smith & Jennifer Y, 2022. "Location bias contributes to functionally selective responses of biased CXCR3 agonists," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    6. Tobias Benkel & Mirjam Zimmermann & Julian Zeiner & Sergi Bravo & Nicole Merten & Victor Jun Yu Lim & Edda Sofie Fabienne Matthees & Julia Drube & Elke Miess-Tanneberg & Daniela Malan & Martyna Szpako, 2022. "How Carvedilol activates β2-adrenoceptors," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    7. Daniel T. D. Jones & Andrew N. Dates & Shaun D. Rawson & Maggie M. Burruss & Colin H. Lipper & Stephen C. Blacklow, 2023. "Tethered agonist activated ADGRF1 structure and signalling analysis reveal basis for G protein coupling," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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